Pancreatic cancer progresses over many years, which offers the opportunity for early detection and prevention. Studies have identified elevated body mass index (BMI) as a risk factor for pancreatic cancer. Lower body weights resulting from calorie restriction have long been associated with extended life expectancy and reduced tumor incidence in laboratory animals. Chronic and intermittent calorie restriction have a powerful protective effect against tumor development. This proposal addresses the hypothesis that intermittent calorie restriction will prevent the development and delay progression of preneoplastic to neoplastic lesions by altering select biomarkers. The Kras;Pdx-1Cre mouse model provides an opportunity to study the efficacy of prevention strategies during the preinvasive state. The specific aims are: 1. To determine the effects of intermittent caloric restriction/refeeding and chronic restriction on the developmental progression of preneoplastic to neoplastic lesions in the K-ras;Pdx-1Cre transgenic mice relative to ad libitum fed mice. 2. Determine biomarker levels during each stage of PanIn progression to advanced lesions and whether chronic and intermittent calorie restriction modifies these biomarkers by measuring: a) serum concentrations of IGF-1 and IGFBP-3, b) the extent of proliferation and apoptosis in the pancreases from K-ras;Pdx-1Cre transgenic mice, c) IGF-1 and IGFBP-3 protein levels in pancreatic ductal cells, and d) activation of EGFR, Ras/MAPK, and PI3K/Akt signaling in pancreatic ductal cells using the cutting edge matrix assembly tissue array with AQUA software. Starting at 6-weeks mice will be assigned to: Group 1: ad libitum fed mice, Group 2: intermittent calorie restricted/refed mice fed in 2-week intervals at 50% of the ad libitum caloric intake followed by 2 weeks of ad libitum feeding;and Group 3: Chronic calorie restricted pair fed the average daily food intake that corresponds to the 4-wk restriction/refeeding interval of the intermittent calorie restricted mice. At 52 and 64 weeks of age, we will screen all the mice for the presence of a tumor by PET imaging. At 64 weeks mice in aim 1 will be sacrificed for evaluation of PanIn lesions and biomarkers. For aim 2 subgroups of mice will be sacrificed at 16 and 28 weeks of age to determine progressive changes in activation of EGFR, Ras/MAPK, PI3K/Akt, and mTOR and protein expression of IGF-1 and IGFBP-3 in pancreas by tissue array, proliferation, and serum concentrations of IGF-1 and IGFBP-3. Data obtained from this study will provide the first available information on whether calorie restriction will be of benefit for preventing pancreatic cancer and identification of biomarkers altered by this intervention. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is a deadly disease with only 5% of the patients living longer than 5 years. It is a disease with no known cure or strategy to prevent its occurrence. Thus, it is urgent to find ways to prevent this disease. Based upon the success of calorie restriction in preventing many types of cancer, this study will evaluate whether chronic and intermittent calorie restriction will prevent pancreatic cancer by targeting precancerous lesions in a relevant mouse model. Additionally, this study will identify early signaling biomarkers associated with precancerous lesion development and determine whether chronic and intermittent calorie restriction decreased the activation of Ras/MAPK/PI3K, proliferation, apoptosis in the pancreas, and circulating IGF-1.